[unreadable] [unreadable] Mice that lack T-bet, a Th1 transcription factor that controls Th1 lineage commitment, are almost [unreadable] completely protected from developing EAE, a mouse model of multiple sclerosis. However, the degree of protection afforded by loss of T-bet cannot be attributed solely to the loss of the hallmark Th1 cytokine, IFN-y, since mice lacking IFN-y, IFN-yR or Stall actually develop more severe EAE than controls. This discrepancy may be partly attributed to the simultaneous function of T-bet in profoundly inhibiting the production of the protective cytokines IL-4, IL-10 and TGF|3 as well as a function for T-bet in controlling migration and adhesion of effector Th1 cells. It may also relate to a role for T bet in the terminal maturation of NK cells. Thus mice that lack T-bet have a marked increase in Th2 cells, and in levels of two immunosuppressive cytokines, TGFp and IL-10. In contrast, T-bet-/- mice have reduced numbers of mature NK cells and lack NK T cells altogether. T-bet-/- Th1 cells also have altered patterns of expression of certain chemokines and chemokine receptors. Of special interest to us therefore is a further exploration of the factors that account for the striking difference in susceptibility to EAE between T-bet and Statl deficient mice. This will require identification of the cell types, cytokines, chemokines and adhesion molecules involved in mediating protection vs. susceptibility to EAE in these transcription factor mutant strains, and also includes exploring the mechanism by which T-bet inhibits the production of TGFp and IL-10. Whatever the mechanisms, however, the very profound effects of loss of T-bet on EAE warrant a search to establish whether polymorphisms in T-bet are associated with human MS. In contrast to IFN-y and IL-4, little is known about the transcription factors that control the tissue specific expression of the IL-10 gene. This is an important deficiency as a role for this highly immunosuppressive cytokine in autoimmune diseases and in EAE in particular has been well documented and exceeds that of IL-4. We propose to study the regulation of the IL-10 gene in T cells and to identify the transcription factors that directly control its tissue-specific expression. We have three Specific Aims: 1- Explore the basis for the different EAE susceptibility of T-bet- versus Statl deficient mice; 2- Investigate the function of T-bet in Th2 and T regulatory cells; 3- Establish the basis for tissue specific regulation of the IL-10. [unreadable] [unreadable]